Ribosomal proteins are increasingly understood to play important roles in development and disease. Indeed, Mutations in ribosomal proteins have been implicated in a number of human diseases collectively referred to as ribosomopathies, some of which exhibit narrow tissue tropisms whose molecular basis is not yet understood. In particular, we have shown that germ-line ablation of the widely expressed ribosomal protein (RP), Rpl22, causes a strikingly specific defect in the development of the a T cell lineage. This is the only RP mutant identified to date whose germline ablation selectively impairs the development of T cells. Important insights as to how Rpl22 performs such a tissue-restricted developmental function may be gained from a comparison of Rpl22 with its closest vertebrate paralog, Rpl22-Like1 (Like1), whose amino acid sequence is more than 70% identical to that of Rpl22. Of the 78 RP encoding genes identified in yeast, 59 have highly homologous paralogs whose functions have not been assessed in vertebrate development. Our preliminary results show that despite their high degree of sequence identity, systemic loss of the paralogs, Rpl22 and Like1, arrests hematopoiesis at distinct points and by different mechanisms. While Rpl22 knockdown blocks a T cell development in the thymus in a p53-dependent manner, knockdown of Like1 blocks the emergence of hematopoietic stem cells (HSC) in a p53-independent manner. In the current application, we seek to gain insight into how the systemic loss of these highly homologous RP paralogs causes such disparate, tissue- restricted defects in hematopoiesis. We will do so according to the following aims: 1) What is responsible for the selective induction of p53 in developing a lineage T cells in Rpl22-deficient mice? 2) What is the molecular basis for the distinct perturbations of hematopoiesis caused by loss of Rpl22 and its paralog, Like1? and 3) How does loss of Like1 block emergence of HSC?